Research & Educational|Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo

Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo
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Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, The University of Tokyo

Department of Pharmaceutical Sciences

Dean Hiroyuki Arai
(2017.5.16Updated)
*:Medicine science department chair
*:Pharmacy department chair

Laboratory of Organic and Medicinal Chemistry

http://www.f.u-tokyo.ac.jp/~yakka/english/index.html
Prof. T. Ohwada
Lecturer  Y. Otani

Synthesis of novel intelligent molecules bearing peculiar chemical structures and chemical and biological features on the basis of new concepts of organic and medicinal chemistry

Research Topics
  1. Synthesis of new compounds exhibiting characteristic structural features and properties
  2. New reactions to functionalize aromatic compounds based on designed superelectrophiles
  3. Design and synthesis of intelligent molecules, which will have impacts on functions of membrane proteins
  4. Theoretical calculation studies of organic reactions and structural features

Our aims of researches emphasize on design and synthesis of structurally novel organic molecules, which are characteristic in terms of structural (bonding) features and intrinsic functions such as chemical reactivities and biological functions. Designs of such novel molecules are based on our finding new chemistry including ground-state stable non-planar amide peptides and nitrosamines, and structures of multiply positively charged molecules. We study nitrogen-pyramidal amides and related nitrosamines, i.e., molecules that take nonplanar structures, different from the common planar amides. We apply this chemistry to construction of molecules of highly ordered structures such as helix peptide mimetics stable in water. We also develop new chemistry involving dication or trication molecules and apply them as superelectrophiles to synthesize a variety of novel multi-functionalized aromatic compounds, which are pharmaceutically relevant. We are also creating chemical molecules, which will be useful to controlling biological events of membrane proteins such as ion channels, neurotransporters and G-protein-coupled receptors. These molecules also contribute to understanding the phyisiological functions of these membrane proteins. We combine all the experimental projects with computational chemistry, which will lead to deep understanding of the underling chemistry.
Helical structure of artificial amino acid peptide stable in water
Helical structure of artificial amino acid peptide stable in water 
Chemical modulation of functions of membrane proteins
Chemical modulation of functions of membrane proteins  

Laboratory of Synthetic Medicinal Chemistry

http://www.f.u-tokyo.ac.jp/~inoue/e_index.html
Prof. M. Inoue
Assist. Prof. M. Nagatomo
Assist. Prof. H. Itoh
Assist. Prof K. Hagiwara

Total synthesis and functional analysis of biologically active natural products

Research Topics
  1. Development of new synthetic methodologies for total synthesis
  2. Total synthesis of highly oxygenated polycyclic natural products
  3. Total synthesis and functional analysis of ion channel-forming molecules
  4. Total synthesis and functional analysis of antimicrobial molecules
  5. Synthesis of new artificial molecules by modification of natural products templates

Natural products have been tremendously important in biology and human medicine because of their power to modulate signal transductions of biological system. Since the removal of sub-structures of the natural products often leads to significant losses of their activity, total chemical syntheses of their entire structures with a precision at an atomic level are necessary to provide sufficient amounts of material required for biological and medical applications. Architecturally complex natural products with molecular weight over 1000 are capable of highly specific interactions with their target proteins. Therefore, they are powerful agents for selectively controlling intricate biological systems. The goal of our research program is efficient, practical and flexible syntheses of gigantic natural molecules, which include highly oxygenated polycyclic natural products as well as ion channel-forming peptides. At the core of this research program is the development of new strategies for assembling architecturally complex natural products in a concise fashion. These synthetic developments would enable unified synthesis of new artificial analogs by modification of natural products templates. The new synthetic methods for the natural products and the synthetic analogs will allow us to tailor and enhance their drug like properties, to gain control over diverse signal transductions thereby offering new research methods for the study of life science.
Total synthesis of highly oxygenated polycyclic natural products
Total synthesis of highly oxygenated polycyclic natural products 
Total synthesis and functional analysis of biologically active peptides
Total synthesis and functional analysis of biologically active peptides 

Laboratory of Synthetic Organic Chemistry

http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
Prof. M. Kanai
Lecturer K. Oisaki
Lecturer S. Kawashima
Assist. Prof. Y. Shimizu
Assist. Prof. K. Yamatsugu

Catalysis for clean, robust, and concise complex molecule synthesis

Research Topics
  1. Development of new catalysis to facilitate complex molecule synthesis
  2. Clean, robust, and concise synthesis of pharmaceuticals and their leads
  3. Catalytic H2 and O2 activation
  4. Conceptually new approach to promote human health

The main theme of our research is the development of revolutionary catalyses facilitating new drug design and synthesis. In this direction, we would like to promote human health based on the catalysis development. Chemical synthesis in 21st century should be clean, robust, and concise, no matter how complex the target molecules are. The "ideal synthesis" will be only possible by new catalytic methodologies. Moreover, new catalyses will expand the diversity of readily available building blocks, leading to structurally novel artificial drug design. Sustainability based on new catalysis is another direction of our research. Specifically, we are interested in catalytic activations of small molecules such as H2 and O2.
New Catalysis and Drug Lead Discovery/Optimization
New Catalysis and Drug Lead Discovery/Optimization 
Respiratory C-C Bond-Forming Catalysis
Respiratory C-C Bond-Forming Catalysis 
Iterative Polyol Synthesis
Iterative Polyol Synthesis 

Laboratory of Natural Products Chemistry

http://www.f.u-tokyo.ac.jp/~tennen/index-e.html
Prof. I. Abe
Assist. Prof. T. Awakawa
Assist. Prof. H. Nakamura

We establish the mechanisms of natural product biosynthesis as a science in their own right, to construct a rational system for the production of new and useful substances

Research Topics
  1. The biosynthesis and bioengineering of medicinal natural products
    (genome mining, engineered biosynthesis)
  2. The enzyme biocatalysts (structure-function analysis, enzyme engineering, mechanistic studies)
  3. The search for bioactive substances and isolation/structure determination

Natural organic compounds, prominent among which are antibiotics such as penicillin, are gifts from nature, and the benefits they have bestowed upon humankind as sources for the pharmaceuticals, etc., that maintain health is inestimable. In our laboratory, we study the process of biosynthesis of natural organic compounds produced by plants and microorganisms, using not only the foundation discipline of organic chemistry, but also incorporating the methods of biochemistry and molecular biology in an effort to understand the enzymes that catalyze each biosynthesis reaction and the functions and control mechanisms of the genes that govern their expression at the molecular level. In addition, we are expanding our research into "biosynthesis engineering," by which rational systems for the biological production of new and useful substances can be designed and constructed, based on the mechanisms of biosynthesis that have been brought to light. We also are carrying out research on the mechanisms by which the bioactivity of natural products is expressed, while at the same time searching for natural products that are active in intracellular signaling.
Concept of  biosynthesis engineering,  by which non-natural compounds are generated
Concept of biosynthesis engineering, by which non-natural compounds are generated 
Plant polyketide based on crystalline structure function control of synthetic enzymes and the production of substances
Plant polyketide based on crystalline structure function control of synthetic enzymes and the production of substances 

Laboratory of Advanced Elements Chemistry

http://www.f.u-tokyo.ac.jp/~kisoyuki/
Prof. M. Uchiyama
Lecturer K. Miyamoto
Assist. Prof. K. Hirano
Assist. Prof. T. Saito
Assist. Prof. C. Wang

Understanding of chemical phenomena at the atomic and electron levels and creation of a new science of materials through flexible construction of molecules

Research Topics
  1. Development of advanced molecular transformation methods supporting materials science and life sciences (methodology development/synthetic chemistry)
  2. Periodic table-traversing chemistry that transcends the frameworks of organic chemistry, inorganic chemistry, and metallic chemistry (elements chemistry)
  3. Elucidation of the structural chemistry of intermediates and transitional states (physical chemistry, spectroscopy, theoretical calculation)
  4. Design and production of materials founded on synthetic chemistry, spectroscopy, and computational chemistry (materials science/life sciences)

Our laboratory focuses on understanding the properties and phenomena of substances by "language of chemistry" such as molecules, atoms, and electrons (Seeing /Knowing); on developing reactions that manipulate the bonds between atoms completely in control (Designing); and on producing functional materials (Producing).
In our laboratory, we strive to develop technologies for the precise chemical conversion of tiny, tiny molecules less than 1 billionth of a meter in size (nanometer scale; nm). Thanks to recent advances in spectroscopy and theoretical calculation, it is getting possible to accurately predict and reproduce snapshots of the state of the electrons that form materials, as well as of reactions between molecules. With the 3 methods, namely, synthetic chemistry, spectroscopy, and theoretical calculation as the pillars of our science, we expand upon elements chemistry in an interdisciplinary manner as we meet the challenges of elucidating life phenomena and creating a new materials science.
Developing new reactions and designing/producing new materials based on computational chemistry and theoretical chemistry (Adopted for the cover of Chemistry: A European Journal)
Developing new reactions and designing/producing new materials based on computational chemistry and theoretical chemistry (Adopted for the cover of Chemistry: A European Journal) 
Life sciences and materials science that open new frontiers in basic organic chemistry and elemental chemistry
Life sciences and materials science that open new frontiers in basic organic chemistry and elemental chemistry 

Laboratory of Medicinal Plant Chemistry (Experimental Station for Medicinal Plant Studies)

http://www.f.u-tokyo.ac.jp/~oriharay/index.htm
Assoc. Prof. Y. Orihara

An overall analysis is made of the old-yet-new drugs known as "medicinal plants" (crude drugs) to develop new ways of using them (utilizing the resources in the Experimental Station for Medicinal Plant Studies)

Research Topics
  1. The cultivation of medicinal plants and tissue cultures
  2. The production of useful secondary metabolites, using plant tissue culture technology
  3. Chemistry and biosynthesis of plant-derived biologically active substances

Since prehistoric times, plants have been the principal material used as drugs by humankind. Many have fallen by the wayside through a long process of trial and error (human experiments), and the ones that remain can be considered the crude drugs of the present day. In recent years, the percentage of all drugs accounted for by antibiotics and biologics has increased, but the importance of plant-derived pharmaceuticals is by no means diminished and has led to the discovery of new drugs such as Taxol and vinblastine. Thus, the study of medicinal plants is by no means completed, and is continuing to evolve.
The Experimental Station for Medicinal Plant Studies, formally established in 1973, is located adjacent to the Kemigawa Athletic Ground. The saplings transplanted there back then have grown large and now form a dense enclosure of trees around the garden.
At the research lab in Hongo, we conduct research on the production of useful secondary metabolites using plant tissue culture technologies (from the induction of culture cells to the production of substances). Some of the research topics we are currently pursuing are the biosynthesis of diterpene constituents from Gymnosperm plant cultured cells, the production and biosynthesis of diterpene alkaloids using cultured tissue of monkshood, the production and biosynthesis of phenylethanoids using cultured cells of olive, and the production of biologically active constituents of Egyptian medicinal plants by means of plant tissue culture technologies.
Aconitum japonicum cultured root
Aconitum japonicum cultured root 
The sweetener glycyrrhizin is contained in the roots and stolons of Glycyrrhiza uralensis Fisher
The sweetener glycyrrhizin is contained in the roots and stolons of Glycyrrhiza uralensis Fisher 

Laboratory of Bioanalytical Chemistry

http://www.f.u-tokyo.ac.jp/~funatsu/index_e.html
Prof. T. Funatsu
Lecturer M. Tsunoda
Assist. Prof. K. Okabe
Assist. Prof. R. Iizuka

We measure the functions of biomolecules at the level of a single molecule to elucidate vital functions

Research Topics
  1. Research on the principles of action by which biomolecular machines such as molecular chaperonin and ribosomes operate
  2. Single-molecule fluorescence imaging of intracellular mRNA processing and transport
  3. Development of micro nanodevices for analyzing the functions and interactions of biomolecules

In order to understand living organisms, it is necessary to conduct research at a variety of different levels. The lowest level is that at which biomolecules such as proteins and DNA work. When these come together, biological supramolecules, cells, organs, and the like are created, while at the higher end, individual organisms, societies, and ecosystems are constituted. We focus on the level of the smallest unit, the "biomolecule," together with the level of the "cell," at which life functions are first expressed, to find answers to questions like "By what mechanisms do biomolecules function?" and "When they aggregate, what kinds of systems do they construct?" Concretely speaking, we bind a fluorescent dye to a single biomolecule and observe it with a sensitive fluorescence microscope. Some biomolecules can exhibit their functions even at the level of the single molecule. For example, the motor protein known as kinesin moves on rail proteins called microtubules. Humankind does not at this point in time possess the technology for creating this kind of molecular machine, but we believe that humankind will be able to make this kind of molecular machine in the near future through research on the motor protein. On the other hand, self-assembly of a variety of different biomolecules creates complex systems which differ greatly from manmade ones. By researching such biological systems, we close in on the mysteries of life.
Fluorescence microscope system for imaging single molecules within living cells
Fluorescence microscope system for imaging single molecules within living cells 
The principle of single-molecule imaging of enzyme reaction (ATPase) using evanescent illumination
The principle of single-molecule imaging of enzyme reaction (ATPase) using evanescent illumination 

Laboratory of Physical Chemistry

http://ishimada.f.u-tokyo.ac.jp/public_html/
Prof. I. Shimada
Assoc. Prof. N. Nishida
Assist. Prof. T. Ueda
Assist. Prof. Y. Kofuku

We develop original methods centered on nuclear magnetic resonance to elucidate life phenomena from new perspectives

Research Topics
  1. Analysis of interactions between membrane proteins and their specific ligands
  2. Identification of the interface of proteins that interacts with heterogeneous macromolecules in vivo
  3. Analysis of the interaction between molecules that govern cell adhesion and the extracellular matrix
  4. Development of methods for accurately identifying the bonding interfaces between proteins and biomolecule complexes

The Laboratory of Physical Chemistry focuses on important life phenomena in living organisms, in which protein interactions play vital roles. Our goal is to reveal the mechanisms of the phenomena, by demonstrating what kinds of biomolecules (other proteins, nucleic acids, sugars, lipids) the proteins interact, with how much binding affinity, and through which specific parts of the protein. We apply structural biological techniques centered on nuclear magnetic resonance (NMR), to determine the interaction site on the protein to a resolution on the order of angstroms, making it possible to explain the functions of proteins at the atomic level. These data are valuable information for rational drug design, and therefore, our research is highly important from the clinical and industrial standpoints.
Currently, we focus on the events that occur on the biomembranes and at their periphery. We apply our own original methods to the interactions involving large and heterogeneous molecules that were difficult to analyze by conventional methods, including ion channels, GPCR, and receptors that recognize heterogeneous extracellular matrix, such as collagen and hyaluronic acid. Anyone who is interested is welcome to take a tour of our laboratory.
Schematic drawing of our method for analyzing the KcsA ‒ AgTx2 interaction, using bead-linked proteoliposomes
Schematic drawing of our method for analyzing the KcsA ‒ AgTx2 interaction, using bead-linked proteoliposomes 
Model of a CPD photolyase ‒ DNA complex constructed on the basis of the results of NMR analysis
Model of a CPD photolyase ‒ DNA complex constructed on the basis of the results of NMR analysis 

Laboratory of Health Chemistry

https://sites.google.com/site/eiseikagakuen/
Prof. H. Arai
Lecturer N. Kono
Assist. Prof. K. Mukai
Assist. Prof. Y. Shimanaka
Assist. Prof. S. Uchiyama

Exploration of new functions for biomembranes and their constituent lipids

Research Topics
  1. Molecular mechanism of lipid biosynthesis and homeostasis
  2. Molecular mechanism of membrane dynamics (e.g., endo/exocytosis)
  3. Elucidation of functions of lipid mediators in inflammatory diseases
  4. Identification of new bioactive lipids and elucidation of their functions

Biomembranes serve as barriers that segregate cells from the external environment. They also produce intracellular organelles, and are essential for cellular functions. The Laboratory of Health Chemisty aims to elucidate the physiological functions of lipids, essential constituents of biomembranes. Over 1,000 lipid species exist in biomembranes, and the appropriate balance among them is assumed to be fundamental to stability, activity, and localization of proteins, and regulation of gene expression. We focus on major components of cellular lipids, called phospholipids, and are trying to identify proteins involved in their biosynthesis and homeostasis. We also study the functions of lipids in the dynamic behavior of biomembranes, such as endo/exocytosis.
Various bioactive lipids are formed from membrane phospholipids, and affect a range of biological phenomena and diseases. Our study also focuses on "inflammatory response" which is the underlying condition of lifestyle-related diseases. To better understand the molecular mechanisms underlying inflammation, we are trying to comprehensively clarify when, where and how much lipid mediators are formed in the inflammatory sites using LC-ESI-MS/MS-based lipidomics system.
The functions of membrane lipids
The functions of membrane lipids 
Lipid-related diseases
Lipid-related diseases 

Laboratory of Physiological Chemistry

http://www.f.u-tokyo.ac.jp/~seiri/
Lecturer M. Fukuyama
Assist. Prof. K. Saito
 

G protein-mediated signaling networks and their physiological significance

Research Topics
  1. Identification and characterization of novel families of small G proteins
  2. Molecular mechanisms of endocytic pathway regulated by small G proteins
  3. Molecular mechanisms of the nutrient sensing mediated by small G proteins
  4. Mechanism of protein exit from the endoplasmic reticulum regulated by G proteins

Our laboratory is interested in the molecular mechanisms of signal transduction that underlie human physiology. Abnormal regulation of cellular signaling is often found in human diseases. Pharmaceutical drugs usually work to offset, alleviate, compensate and correct such deranged transduction of signals. Thus, understanding the molecular principles of signal transduction would greatly help to develop new drugs. We take a broad range of experimental techniques that utilize biochemistry, molecular biology, cell biology and molecular genetics. Our research has centered around GTP-binding proteins, so called "G proteins." We wish to expand and deepen our understanding of signaling networks involving G proteins and their physiological significance.
Various G proteins involved in signal transduction pathways
Various G proteins involved in signal transduction pathways 
Endocytosed macromolecules (Alexa488-BSA) in late endosomes fail to reach ASP-1-enriched compartments (lysosomes, ASP-1::DsRed) in the coelomocytes of C.elegans mutants of arl-8.
Endocytosed macromolecules (Alexa488-BSA) in late endosomes fail to reach ASP-1-enriched compartments (lysosomes, ASP-1::DsRed) in the coelomocytes of C.elegans mutants of arl-8. 

Laboratory of Molecular Biology

http://www.f.u-tokyo.ac.jp/~molbio/english/e_index.html
Prof. Y. Gotoh
Assist. Prof. Y. Kishi
Assist. Prof. T. Okazaki
Assist. Prof. D. Kawaguchi
Assist. Prof. M. Higuchi

Our long-term goal is to provide new vistas in immunity and pathogenesis on the basis of glycosciences and to develop new diagnostic and therapeutic tools for currently incurable diseases. The main focuses are on immunology, oncology, and infectious diseases.

Research Topics
  1. Biological function and medical application of mucins, such as MUC21
  2. Immunological significance of C-type lectins, such as MGL/CD301, expressed on dendritic cells and macrophages
  3. Biological roles of glycosidases, such as heparanase, in immunity and cancer
  4. Molecular mechanism of cancer metastases and methods to eradicate micrometastases

To understand the mechanism of disease processes, we focus on cellular interactions. Carbohydrate chains found on cell surfaces and in the extracellular matrix, abundant and extremely variable in modifications, are believed to cause significant impact in these interactions. These carbohydrate chains play vital roles in disease process through specialized molecules such as mucins (heavily glycosylated glycoproteins), lectins (carbohydrate recognition molecules), and glycosidases (degradation enzymes for carbohydrate chains). We discovered a novel mucin (MUC21), lectin (MGL/CD301), and glycosidase (heparanase), and have proved that these molecules were the essential elements in several disease processes including viral infection, hypersensitivity inflammatory diseases, and cancer metastases. By applying modern scientific technologies such as the developments of gene deficient mice, specific monoclonal antibodies, in vitro assays, and analytical techniques, the significant roles of these complex molecules were further established. It is our mission to develop diagnostic tools, therapeutic modalities, and preventive measures, through elucidation the mechanisms of these molecules as they play the pivotal role in the disease processes.

 

 

Laboratory of Genetics

http://www.f.u-tokyo.ac.jp/~genetics/index_e.html
Prof. M. Miura
Assoc. Prof. Y. Yamaguchi
Assist. Prof. T. Katsuyama

Research of development, growth, aging, and behavior from the perspective of cell society

Research Topics
  1. Regulation and function of cell death signaling in development, growth, and aging
  2. Regulation of cell number and size of tissue via programmed cell death
  3. Formation and maintenance of neural network
  4. Metabolic regulation of development and growth
  5. Molecular mechanisms of hibernation
  6. Neural mechanisms of social behavior
Programmed cell death functions in dynamic tissue formation or remodeling. We have revealed that in the embryonic development, or aging process, caspases are activated by various physiological stresses and exert regulatory functions. We aim to reveal how cell society is constructed and maintained during development, growth, and aging process with a particular focus on understanding the regulatory mechanisms and functions of cell death. From the perspective of cell sociology, we are also studying the unique biological phenomena such as neural development, hibernation and behavior by using various model animals. We believe that our research would stimulate and encourage students and researchers to have the breadth of vision for life science research and provide new insights into the molecular logic underlying the formation and maintenance of cell society.
Fig. 1: Caspases are activated in cells exposed to various environmental stresses (Left). To monitor the activation state of caspase in live cells, we generated a genetically encoded sensor for caspase activation based on FRET, named SCAT3 (Right).  Color change from red to blue reflects the activation state of caspase (Left bottom).  Fig. 2: Birth and selection by cell death of neural precursor cells during the development of Drosophila sensory organ  Fig. 3: Live-imaging of apoptosis in the neural tube closure of mouse brain  Fig. 4: Genetic labeling and manipulation of olfactory projection neurons in Drosophila brain
Fig. 1: Caspases are activated in cells exposed to various environmental stresses (Left). To monitor the activation state of caspase in live cells, we generated a genetically encoded sensor for caspase activation based on FRET, named SCAT3 (Right). Color change from red to blue reflects the activation state of caspase (Left bottom). Fig. 2: Birth and selection by cell death of neural precursor cells during the development of Drosophila sensory organ Fig. 3: Live-imaging of apoptosis in the neural tube closure of mouse brain Fig. 4: Genetic labeling and manipulation of olfactory projection neurons in Drosophila brain 

Laboratory of Cell Signaling

http://www.f.u-tokyo.ac.jp/~toxicol/en/index.html
Prof. H. Ichijo*
Assoc. Prof. I. Naguro
Assist. Prof. K. Hattori
Assist. Prof. T. Fujisawa
Assist. Prof. K. Watanabe

From signal transduction to drug discovery

Research Topics
  1. Signal transduction and functions of ASK family proteins
  2. Exploration of novel signaling molecules involved in cell death and stress responses
  3. Molecular mechanisms of pathogenesis induced by dysfunction of stress signaling

The Laboratory of Cell Signaling has been focusing on analyses of the intracellular signal transduction, through which we seek to elucidate molecular basis of human diseases and identify novel drug targets. Our current research mainly focuses on the pathophysiological roles of stress responsive signals in various diseases such as cancers, immune disorders, cardiovascular diseases and neurodegenerative diseases. In addition to molecular genetic tools such as mice, flies and worms as well as basic experimental techniques from molecular cloning to protein biochemistry, we always incorporate novel analytic technologies such as mass spectrometry-based proteomic analysis and genome-wide RNAi screening systems into our research exploring"target molecules and molecular mechanisms". By taking advantage of such experimental approaches, we aim to open up new fields in pharmaceutical sciences with paying attention to whole body physiology, diseases and drug discovery.
MAP kinase pathways in mammals
MAP kinase pathways in mammals 
Analysis of stress signaling at levels of molecules, cells and bodies
Analysis of stress signaling at levels of molecules, cells and bodies 

Laboratory of Protein Metabolism

http://www.f.u-tokyo.ac.jp/~tanpaku/index-e.html
Prof. S. Murata
Assoc. Prof. H. Yashiroda
Assist. Prof. J. Hamazaki
Assist. Prof. S. Hirayama

Shedding light on the various biological phenomena controlled by proteolysis

Research Topics
  1. The action mechanism of the proteasome, a multisubunit macromolecular complex responsible for regulated protein degradation in eukaryotic cells
  2. Proteasome dysfunction in human diseases and aging
  3. The mechanism of T-cell selection by the thymus-specific proteasome
  4. The mechanism for the disposal of abnormal proteins by the ubiquitin-proteasome system

Laboratory of Protein Metabolism explores the regulatory mechanism of cellular functions by the ubiquitin-proteasome system, which is the major proteolytic machinery in eukaryotic cells. The lab's main interest is the proteasome, which is an elaborate proteolytic enzyme that degrades ubiquitinated proteins and is a key regulator of physiological events. The questions we are interested in are, how is the proteasome regulated, how does it assemble, and how is it involved in human diseases. To this end, we make use of experimental techniques including biochemistry, molecular biology, cell biology, genetic engineering of the mouse, fly genetics, and yeast genetics. In recent years, there has been accumulating evidence indicating a close relationship between the ubiquitin-proteasome system and human diseases such as cancer, neurodegenerative diseases, immune disorders, and aging. The goal of our research activities is to provide new molecular bases for the development of drugs for such diseases.
Physiological roles of the ubiquitin-proteasome mediated protein degradation in eukaryotes
Physiological roles of the ubiquitin-proteasome mediated protein degradation in eukaryotes 
Proteasome dysfunction and human diseases
Proteasome dysfunction and human diseases 

Laboratory of Cellular Biochemistry (Institute of Medical Science, Division of Cellular and Molecular Biology)

http://www.traf6.com/
Prof. J. Inoue

Elucidating the intracellular signaling involved in disease development, with the goal of drug discovery

Research Topics
  1. Transcription factor NF-κB activation signal mediated by TRAF family
  2. Signal transmission by ubiquitination
  3. Malignant progression of cancer and signaling
  4. Bone metabolism disorders and signaling
  5. Autoimmune diseases and signaling

The themes pursued in our laboratory are related to "cancer", "immunity", and "bones", since TRAF6 and NF-κB, which we are interested in, are profoundly involved in tumorigenesis, immune regulation, and bone metabolism. Upon cytokine stimulation, TRAF6 acts as E3 ubiquitin ligase to generate Lys-63-linked polyubiquitin chains, which do not induce proteasomal degradation rather act as platforms for formation of active signal complexes leading to the activation of NF-κB. A number of serious human diseases are caused by various kinds abnormalities in bone metabolism and immunodeficiencies. We were able to reproduce diseases similar to these human diseases in TRAF6- or NF-κB-deficient mice, indicating that TRAF6/NF-κB signals are essential for normal bone formation and the establishment of immunity. Abnormal activation of NF-κB also plays a critical role in the onset and progression of leukaemias and many other cancers. We are trying to elucidate how dysregulation of the TRAF6/NF-κB signals leads to malignant transformation, immunoregulation, and bone metabolism at the molecular level and conducting numerous experiments on gene transfer into cultured cells, aiming to put the results to use in drug discovery and the diagnosis and treatment of diseases.
TRAF6 is activated by extracellular stimuli and acts as E3 ubiquitin ligase to conjugate Lys-63-linked polyubiquitin chains to several signal transducer proteins including NEMO, TAK1, IRAK, and TRAF6 itself. These polyubiquitin chains become the scaffolding for interactions of various proteins without inducing proteolysis, and thereby promote the formation of signal complexes to transmit signals. As a result, the transcription factor NF-κB and the protein kinases known as MAPKs become activated, which induces and regulates many important biological processes. Dysregulation of these signal pathways can cause cancer and other serious diseases.
TRAF6 is activated by extracellular stimuli and acts as E3 ubiquitin ligase to conjugate Lys-63-linked polyubiquitin chains to several signal transducer proteins including NEMO, TAK1, IRAK, and TRAF6 itself. These polyubiquitin chains become the scaffolding for interactions of various proteins without inducing proteolysis, and thereby promote the formation of signal complexes to transmit signals. As a result, the transcription factor NF-κB and the protein kinases known as MAPKs become activated, which induces and regulates many important biological processes. Dysregulation of these signal pathways can cause cancer and other serious diseases. 
X-ray images of a normal mouse (left) and TRAF6 knockout mouse (right). The TRAF6 knockout mouse has unusually high bone density compared to the normal mouse, a condition known as osteopetrosis. This is because the TRAF6-deficient mice cannot generate the osteoclasts, which absorb bones, because RANK-induced activation of NF-κB and MAPKs in osteoclast progenitor cells is abrogated in the absence of TRAF6. Dysregulation of osteoclastogenesis is involved in the progression of rheumatoid arthritis, osteoporosis, and bone metastasis of cancer cells.
X-ray images of a normal mouse (left) and TRAF6 knockout mouse (right). The TRAF6 knockout mouse has unusually high bone density compared to the normal mouse, a condition known as osteopetrosis. This is because the TRAF6-deficient mice cannot generate the osteoclasts, which absorb bones, because RANK-induced activation of NF-κB and MAPKs in osteoclast progenitor cells is abrogated in the absence of TRAF6. Dysregulation of osteoclastogenesis is involved in the progression of rheumatoid arthritis, osteoporosis, and bone metastasis of cancer cells. 

Laboratory of Pathological Cell Biology

Prof. H. Arai
Assoc. Prof. T. Taguchi

Molecular basis of intracellular membrane traffic and its pathophysiological relevance

Research Topics
  1. Molecular basis of vectorial endosomal membrane traffic
  2. Recycling endosomes in physiology and pathophysiology
  3. Screening of low molecular weight compounds that regulate intracellular membrane traffic

Eukaryotic cells have elaborate internal connections of organelles to synthesize proteins and lipids, to release secreted proteins, to take up nutrients, and to degrade internalized molecules. Membrane proteins and lipids move from organelle to organelle using membrane-bound vesicles. Defects in this transport system, called "membrane traffic", have been associated with a number of human diseases, including cancer and diabetes. Recent studies reveal that many pathogens, such as bacteria and viruses, exploit membrane traffic to invade and proliferate in host cells. Therefore, understanding of how membrane traffic is regulated in cells at molecular level is essential to cure diseases and to cope with pathogens.
We have shown that recycling endosomes (REs) serve as intersections of a number of essential membrane traffic, such as recycling-, exocytotic-, and retrograde-pathways, and sort proteins and lipids to the correct destinations. We identify critical molecules that manipulate the membrane traffic through REs, such as evectin-2, and now translate our cellular insights into pathophysiological applications.
Figure 1: intracellular transport of cholera toxin B-subunit (CTxB) Fluorescent-labeled CTxB (in red) was taken up by COS-1 cells, and monitored its delivery for the indicated times. After a 15-min chase, CTxB reached REs that are spatially encircled by the Golgi (GM130 in green). After a 75-min chase, CTxB reached the Golgi. Scale bar, 10 μm
Figure 1: intracellular transport of cholera toxin B-subunit (CTxB) Fluorescent-labeled CTxB (in red) was taken up by COS-1 cells, and monitored its delivery for the indicated times. After a 15-min chase, CTxB reached REs that are spatially encircled by the Golgi (GM130 in green). After a 75-min chase, CTxB reached the Golgi. Scale bar, 10 μm 
Figure 2: evectin-2 is essential for CTxB delivery to the Golgi In cells depleted of evectin-2, the traffic from REs to the Golgi was significantly impaired. Even after a 90-min chase, CTxB was entrapped at REs. Scale bar, 10 μm
Figure 2: evectin-2 is essential for CTxB delivery to the Golgi In cells depleted of evectin-2, the traffic from REs to the Golgi was significantly impaired. Even after a 90-min chase, CTxB was entrapped at REs. Scale bar, 10 μm 


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